Class I and class II HDACs are zinc metalloenzymes that catalyse the hydrolysis of acetylated lysine residues. In histones, this returns lysines to their normal protonated state and is a global mechanism of eukaryotic transcriptional control, resulting in tight packaging of DNA in the nucleosome. Additionally, reversible lysine acetylation is an important regulatory process for non-histone proteins. Thus, compounds which are able to modulate HDAC have important therapeutic potential.
Two natural product depsipeptides, FK228 and Spiruchostatin A, have been reported to have potential as HDAC inhibitors. However, there are limited opportunities to chemically modify or optimize the biological or physicochemical properties of these natural products in order to provide analogues that have the potential for use in treating human diseases.